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Treatment of Hepatitis C With Interferon- and Ribavirine in a Patient With Long-Term Clozapine Treatment

TO THE EDITOR: In patients with severe mental illness, there is often an elevated incidence of hepatitis C.¹ The available treatment for hepatitis C is the combination of interferon- (IFN-) and ribavirin. Clozapine treatment has been found to be effective for refractory schizophrenia. Unfortunately, both IFN- and clozapine represent an increased risk of developing agranulocytosis, and their combined treatment further elevates this risk.^2,3 Therefore, a combination of IFN- with clozapine has rarely been used in clinical practice and, consequently, has hardly been investigated. To the best of our knowledge, there are only a few case reports on this issue that have reported the development of agranulocytosis.^4,5 The need for treating hepatitis C in patients with severe mental illness is also evident because of the possible risk of cirrhosis and hepatocellular carcinoma. Clozapine is often the only effective treatment (when other antipsychotics have already turned out to be ineffective), and, consequently, changing the antipsychotic medication would lead to a worsening of the patient’s psychiatric condition. Therefore, using clozapine and IFN- at the same time is the only possible choice for a certain patient group.

Case Report
A 25-year-old Caucasian male patient with hepatitis C was sent for consultation to our outpatient clinic (Department of Psychiatry, Savonlinna Central Hospital, Finland) for evaluation for IFN- therapy. His first psychotic symptoms had appeared 6 years earlier, for which he had been hospitalized. One year later, clozapine treatment was started (Leponex; Novartis), up-titrated to 700 mg/day) since the patient had not responded to first-line antipsychotics. The patient also had adjuvant lamotrigine (Lamictal 200mg/day; GlaxoSmithKline), and bisoprolol (Emconcor 5 mg/day; Merck) as an additional drug treatment. Before the evaluation, the psychiatric condition had remained stable for years with this clozapine–lamotrigine treatment.

During his first hospital treatment period, the hepatitis C infection (HCV genotype 3a) was diagnosed; the most probable route of the infection was thought to be intravenous drug use 1 year earlier. In the 1 year before the evaluation, during which the patient was considered to be suitable for IFN-treatment, the number of white blood cells (WBC) had ranged between 6.2 and 10.1 x 10⁹/l and absolute neutrophil count (ANC) between 3.17 and 6.82 x 10⁹/l. ASAT, ALAT, and HCV-RNA were 61 U/I, 143 U/I, and 3.42 x 10⁷ IU/ml 3 months, respectively, before the treatment. During INF- treatment, the patient’s psychiatric condition, as well as WBC and ANC, were evaluated weekly and HCV-RNA 3 months after the beginning and 6 months after the end of the treatment. Additional blood-cell evaluations were carried out when needed for safety precautions. His psychiatric condition remained stable during the entire treatment. The 24-week treatment for hepatitis C was started with peg-interferon-2b (PegIntron; Schering-Plough) 120 µg s.c. weekly, but lowered to 100 µg at Week 7, and 80 µg at Week 13, and continued with 100 µg from Week 14 until the end of treatment. Ribavirin (Copegus; Roche/Rebetol, Schering-Plough) 1,000 mg/day was used continuously.

As the IFN- treatment started, the WBC and ANC dropped gradually from baseline levels (WBC: 7.2 x 10⁹/l; ANC: 4.55 x 10⁹/l), being lowest (WBC: 2.6 x 10⁹/l and ANC: 1.02 x 10⁹/l) at Week 21, but rising after that, toward the end of the IFN- treatment period (WBC: 3.8 x 10⁹/l; ANC: 2.19 x 10⁹/l). Within 22 days after the last INF- dose, at Week 27, from the beginning of the IFN- treatment, the WBC and ANC had risen to 5.5 x 10⁹/l and 3.75 x 10⁹/l, respectively. Transaminases normalized within 3 weeks from the beginning of the IFN treatment: HCV-RNA was <600 IU/ml (undetectable) 3 months after the beginning of the INF- treatment and <15 IU/ml 6 months after the last dose of the treatment.

Discussion
In our patient, WBC values rose rapidly after the IFN treatment had ended, and thus it seems reasonable to assume that the decrease in WBC/ANC was due to the IFN treatment. According to the clozapine treatment guidelines, clozapine treatment should have been interrupted at Weeks 8, 14, and 21 of the IFN treatment. In our case ANC/WBC immediately returned to normal at Weeks 8 and 14, but started to be continuously critically decreased from Week 20. Thus, with shorter IFN treatment (12–16 weeks),⁶ the question of whether or not to stop clozapine treatment at Week 21 because of low WBC/ANC could have been avoided. Further studies are needed to define clinical guidelines on the most suitable duration of IFN treatment periods in connection with the treatment for hepatitis C in patients with severe mental illness who are already undergoing antipsychotic treatment with clozapine.⁶

REFERENCES

1. Rosenberg SD, Goodman LA, Osher FC, et al: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health 2001; 91:31–37[Abstract]
2. Casato M, Pucillo LP, Leoni M, et al: Granulocytopenia after combined therapy with interferon with angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity. Am J Med 1995; 99:386–391[CrossRef][Medline]
3. Gerson S, Lieberman JA, Friedenberg WR, et al: Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet 1991; 338:262–263[CrossRef][Medline]
4. Hoffman RM, Ott S, Parhofer KG, et al: Interferon--induced agranulocytosis in a patient on long-term clozapine therapy. J Hepatol 1998; 29:170[CrossRef][Medline]
5. Zung S, Hong M, Forte G: Agranulocytosis induced by interferon- and ribavirin in a patient with schizophrenia using clozapine. Rev Bras Psiquiatr 2006; 28:80–85[Medline]
6. Dalgard O, Mangia A: Short-term therapy for patients with hepatitis C virus genotype 2 or 3 infections. Drugs 2006; 66:1807–1815[CrossRef][Medline]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Articles by Liukkonen, T. Articles by Timonen, M. PubMed Citation Articles by Liukkonen, T. Articles by Timonen, M. Schizophrenia Spectrum Disorders Syndromes Secondary to General Medical Disorders Atypical Neuroleptics

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